Heterocyclic benzodiazepine CGRP receptor antagonists

ABSTRACT

Compounds of formula I: 
                         
(where variables R 2 , R 7 , D, W, X, Y and Z are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage entry under 35 U.S.C. §371 ofPCT/US06/28835, filed Jul. 25, 2006, which claims benefit under 35U.S.C. §119(e) to provisional application 60/704,208, filed Jul. 29,2005.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human α-CGRP-(8-37), afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁, whereas the linear analogue of CGRP,diacetamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂. CGRP is a potent vasodilator that has been implicatedin the pathology of cerebrovascular disorders such as migraine andcluster headache. In clinical studies, elevated levels of CGRP in thejugular vein were found to occur during migraine attacks (Goadsby etal., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on thesmooth muscle of intracranial vessels, leading to increasedvasodilation, which is thought to be the major source of headache painduring migraine attacks (Lance, Headache Pathogenesis: Monoamines,Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers,1997, 3-9). The middle meningeal artery, the principle artery in thedura mater, is innervated by sensory fibers from the trigeminal ganglionwhich contain several neuropeptides, including CGRP. Trigeminal ganglionstimulation in the cat resulted in increased levels of CGRP, and inhumans, activation of the trigeminal system caused facial flushing andincreased levels of CGRP in the external jugular vein (Goadsby et al.,Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the duramater in rats increased the diameter of the middle meningeal artery, aneffect that was blocked by prior administration of CGRP(8-37), a peptideCGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).Trigeminal ganglion stimulation increased facial blood flow in the rat,which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669,93-99). Electrical stimulation of the trigeminal ganglion in marmosetproduced an increase in facial blood flow that could be blocked by thenon-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol.,2000, 129, 420-423). Thus the vascular effects of CGRP may beattenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigetninal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, asthma(Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al.,Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993,67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30(8), 1794-1798); opiate withdrawal syndrome (Salmon et al., NatureNeurosci., 2001, 4(4), 357-358) morphine tolerance (Menard et al., J.Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chenet al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166,1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000,43 (3), 137-143); encephalitis, brain trauma, ischaemia, stroke,epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol.of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds.,Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), neurogeniccutaneous redness, skin rosaceousness and erythema. Of particularimportance is the acute or prophylactic treatment of headache, includingmigraine and cluster headache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I:

(where variables R², R⁷, D, W, X, Y and Z are as defined herein) usefulas antagonists of CGRP receptors and useful in the treatment orprevention of diseases in which the CGRP is involved, such as headache,migraine and cluster headache. The invention is also directed topharmaceutical compositions comprising these compounds and the use ofthese compounds and compositions in the prevention or treatment of suchdiseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to CGRP antagonists which includecompounds of Formula I:

wherein:Z is selected from:

D is independently selected from N and C(R¹);R¹ is independently selected from:

-   1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl,    and heterocycle, unsubstituted or substituted with one or more    substituents each independently selected from:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents each        independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C¹⁻³ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and,    -   v) O(CO)R⁴;-   2) aryl or heteroaryl, unsubstituted or substituted with one or more    substituents each independently selected from:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents each        independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and    -   v) O(CO)R⁴;        where any two independent R¹ and the atom or atoms to which they        are attached optionally join to form a ring selected from C₃₋₆        cycloalkyl, aryl, heterocycle, and heteroaryl;        R² is independently selected from H and:    -   1) C₁₋₆ alkyl,    -   2) C₃₋₆ cycloalkyl,    -   3) aryl, unsubstituted or substituted with 1-5 substituents        where the substituents are independently selected from R⁴,    -   4) heteroaryl, unsubstituted or substituted with 1-5        substituents where the substituents are independently selected        from R⁴,    -   5) heterocycle, unsubstituted or substituted with 1-5        substituents where the substituents are independently selected        from R⁴,    -   6) (F)_(p)C₁₋₃ alkyl,    -   7) halogen,    -   8) OR⁴,    -   9) O(CH₂)_(s)OR⁴,    -   10) CO₂R⁴,    -   11) (CO)NR¹⁰R¹¹,    -   12) O(CO)NR¹⁰R¹¹,    -   13) N(R⁴)(CO)NR¹⁰R¹¹,    -   14) N(R¹⁰)(CO)R¹¹,    -   15) N(R¹⁰)(CO)OR¹¹,    -   16) SO₂NR¹⁰R¹¹,    -   17) N(R¹⁰) SO₂R¹¹,    -   18) S(O)_(m)R¹⁰,    -   19) CN,    -   20) NR¹⁰R¹¹,    -   21) N(R¹⁰)(CO)NR⁴R¹¹, and    -   22) O(CO)R⁴;        where any two independent R² on the same or adjacent atoms        optionally join to form a ring selected from cyclobutyl,        cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,        thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl;        R⁷ is selected from:    -   1) H, C₀-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl        and heterocycle, unsubstituted or substituted with one or more        substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R¹¹,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO2R¹¹        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹,        -   v) O(CO)R⁴; and    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R¹¹,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰) SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹, and        -   v) O(CO)R⁴;            R⁴ is independently selected from: H, C₁₋₆ alkyl,            (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and            benzyl, unsubstituted or substituted with halogen, hydroxy            or C₁-C₆ alkoxy;            M is —NH— or is a bond;            K is —CH₂— or is a bond;            W is O, NR⁴ or C(R⁴)₂;            X is C or S;            Y is O, (R⁴)₂, NCN, NSO₂CH₃ or NCONH₂, or Y is O₂ when X is            S;            R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents        where the substituents are independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and    -   v) O(CO)R⁴;        J is a bond, C(R⁶)₂, O or NR⁶;        V is selected from a bond, C(R⁶)₂, O, S(O)_(m), NR⁶,        C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), C(R⁶)₂—N(R⁶), C(R⁶)═N, N(R⁶)—C(R⁶)₂,        N═C(R⁶), and N(R⁶)—N(R⁶);        G-L is selected from: N, N—C(R⁶)₂, C═C(R⁶), C═N, C(R⁶),        C(R⁶)—C(R⁶)₂, C(R⁶)—C(R⁶)₂—C(R⁶)₂, C═C(R⁶)—C(R⁶)₂,        C(R⁶)—C(R⁶)═C(R⁶), C(R⁶)—C(R⁶)₂—N(R⁶), C═C(R⁶)—N(R⁶),        C(R⁶)—C(R⁶)═N, C(R⁶)—N(R⁶)—C(R⁶)₂, C═N—C(R⁶)₂, C(R⁶)—N═C(R⁶),        C(R⁶)—N(R⁶)—N(R⁶), C═N—N(R⁶), N—C(R⁶)₂—C(R⁶)₂, N—C(R⁶)═C(R⁶),        N—C(R⁶)₂—N(R⁶), N—C(R⁶)═N, N—N(R⁶)—C(R⁶)₂ and N—N═C(R⁶);        Q is independently selected from:        (1) ═C(R^(7a))—,        (2) —C(R^(7a))₂—,        (3) —C(═O)—,        (4) —S(O)_(m)—,        (5) ═N—,        (6) —N(R^(7a))—, and        (7) a bond;        T is independently selected from:        (1) ═C(R^(7b))—,        (2) —C(R^(7b))₂—,        (3) —C(═O)—,        (4) —S(O)_(m)—,        (5) ═N—,        (6) —N(R^(7b))—, and        (7) a bond;        R³ is independently selected from H, substituted or        unsubstituted C₁-C₃ alkyl, F, CN and CO₂R⁴;        R^(7a) and R^(7b) are each independently selected from R², where        R^(7a) and R^(7b) and the atom or atoms to which they are        attached optionally join to form a ring selected from C₃₋₆        cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is        unsubstituted or substituted with 1-10 substituents each        independently selected from R⁶;        R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,        (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and        benzyl, unsubstituted or substituted with halogen, hydroxy or        C₁-C₆ alkoxy, where R¹⁰ and R¹¹ optionally join to form a ring        selected from: azetidinyl, pyrrolidinyl, piperidinyl,        piperazinyl, or morpholinyl, which is ring is unsubstituted or        substituted with 1-5 substituents each independently selected        from R⁴;        p is 0 to 2q+1, for a substituent with q carbons;        m is 0, 1 or 2;        s is 1, 2 or 3;        the dashed line indicates the optional presence of a double        bond;        and pharmaceutically acceptable salts and individual        diastereomers thereof.

Additional embodiments of the invention include CGRP antagonists ofFormula Ia:

where R², R⁷, W, X, Y and Z are as described in Formula I, and D isindependently selected from C(R¹)₂.

Further embodiments of the invention include CGRP antagonists of theFormula Ib:

wherein:D is independently selected from N and C(R¹);R¹ is independently selected from:

-   1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl,    and heterocycle, unsubstituted or substituted with one or more    substituents each independently selected from:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents each        independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and,    -   v) O(CO)R⁴;-   2) aryl or heteroaryl, unsubstituted or substituted with one or more    substituents each independently selected from:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents each        independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and    -   v) O(CO)R⁴;        where any two independent R¹ and the atom or atoms to which they        are attached optionally join to form a ring selected from C₃₋₆        cycloalkyl, aryl, heterocycle, and heteroaryl;        R² is independently selected from H and:    -   1) C₁₋₆ alkyl,    -   2) C₃₋₆ cycloalkyl,    -   3) aryl, unsubstituted or substituted with 1-5 substituents        where the substituents are independently selected from R⁴,    -   4) heteroaryl, unsubstituted or substituted with 1-5        substituents where the substituents are independently selected        from R⁴,    -   5) heterocycle, unsubstituted or substituted with 1-5        substituents where the substituents are independently selected        from R⁴,    -   6) (F)_(p)C₁₋₃ alkyl,    -   7) halogen,    -   8) OR⁴,    -   9) O(CH₂)_(s)OR⁴,    -   10) CO₂R⁴,    -   11) (CO)NR¹⁰R¹¹,    -   12) O(CO)NR¹⁰R¹¹,    -   13) N(R⁴)(CO)NR¹⁰R¹¹,    -   14) N(R¹⁰)(CO)R¹¹,    -   15) N(R¹⁰)(CO)OR¹¹,    -   16) SO₂NR¹⁰R¹¹,    -   17) N(R¹⁰) SO₂R¹¹,    -   18) S(O)_(m)R¹⁰,    -   19) CN,    -   20) NR¹⁰R¹¹,    -   21) N(R¹⁰)(CO)NR⁴R¹¹, and    -   22) O(CO)R⁴;        where any two independent R² on the same or adjacent atoms        optionally join to form a ring selected from cyclobutyl,        cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,        thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl;        R⁷ is selected from:    -   1) aryl unsubstituted or substituted with one or more        substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R¹¹,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰) SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹, and        -   v) O(CO)R⁴;            R⁴ is independently selected from: H, C₁₋₆ alkyl,            (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and            benzyl, unsubstituted or substituted with halogen, hydroxy            or C₁-C₆ alkoxy;            Q is independently selected from:            (1) ═C(R^(7a))—,            (2) —C(R^(7a))₂—,            (3) —C(═O)—,            (4) —S(O)_(m)—,            (5) ═N—, and            (6) —N(R^(7a))—;            T is independently selected from:            (1) ═C(R^(7b))—,            (2) —C(R^(7b))₂—,            (3) —C(═O)—,            (4) —S(O)_(m)—,            (5) ═N—, and            (6) —N(R^(7b))—;            R³ is independently selected from H, substituted or            unsubstituted C₁-C₃ alkyl, F, CN and CO₂R⁴;            R^(7a) and R^(7b) are each independently selected from R²,            where R^(7a) and R^(7b) and the atom or atoms to which they            are attached optionally join to form a ring selected from            C₃₋₆ cycloalkyl, aryl, heterocycle, and heteroaryl, which            ring is unsubstituted or substituted with 1-10 substituents            each independently selected from R⁶;            R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,            (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and            benzyl, unsubstituted or substituted with halogen, hydroxy            or C₁-C₆ alkoxy, where R¹⁰ and R¹¹ optionally join to form a            ring selected from: azetidinyl, pyrrolidinyl, piperidinyl,            piperazinyl, or morpholinyl, which is ring is unsubstituted            or substituted with 1-5 substituents each independently            selected from R⁴;            p is 0 to 2q+1, for a substituent with q carbons;            m is 0, 1 or 2;            s is 1, 2 or 3;            and pharmaceutically acceptable salts and individual            diastereomers thereof.

Still further embodiments of the invention include CGRP antagonistsFormula Ic:

wherein:D is independently selected from N and C(R¹);R¹ is independently selected from:

-   1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl,    and heterocycle, unsubstituted or substituted with one or more    substituents each independently selected from:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents each        independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and,    -   v) O(CO)R⁴;-   2) aryl or heteroaryl, unsubstituted or substituted with one or more    substituents each independently selected from:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents each        independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents each independently selected from R⁴,    -   f) (F)_(p)C₁₋₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰) SO₂R¹¹,    -   r) S(O)_(m)R¹¹,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and    -   v) O(CO)R⁴;        where any two independent R¹ and the atom or atoms to which they        are attached optionally join to form a ring selected from C₃₋₆        cycloalkyl, aryl, heterocycle, and heteroaryl;        R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆        alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,        unsubstituted or substituted with halogen, hydroxy or C₁-C₆        alkoxy;        Q is independently selected from:        (1) ═C(R^(7a))—,        (2) —C(R^(7a))₂—,        (3) —C(═O)—,        (4) —S(O)_(m)—,        (5) ═N—, and        (6) —N(R^(7a))—;        T is independently selected from:        (1) ═C(R^(7b))—,        (2) —C(R^(7b))₂—,        (3) —C(═O)—,        (4) —S(O)_(m)—,        (5) ═N—, and        (6) —N(R^(7b))—;        R^(7a) and R^(7b) are each independently selected from R², where        R^(7a) and R^(7b) and the atom or atoms to which they are        attached optionally join to form a ring selected from C₃₋₆        cycloalkyl, aryl, heterocycle, and heteroaryl, which ring is        unsubstituted or substituted with 1-10 substituents each        independently selected from R⁶;        R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,        (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and        benzyl, unsubstituted or substituted with halogen, hydroxy or        C₁-C₆ alkoxy, where R¹⁰ and R¹¹ optionally join to form a ring        selected from: azetidinyl, pyrrolidinyl, piperidinyl,        piperazinyl, or morpholinyl, which is ring is unsubstituted or        substituted with 1-5 substituents each independently selected        from R⁴;        p is 0 to 2q+1, for a substituent with q carbons;        m is 0, 1 or 2;        s is 1, 2 or 3;        and pharmaceutically acceptable salts and individual        diastereomers thereof.

Embodiments of the present invention also include those wherein J is abond, C(R⁵)₂, O, or NR⁵, and V is a bond, C(R⁶)₂, O, S(O)_(m), NR⁶,C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), C(R⁶)₂—N(R⁶), C(R⁶)═N, N(R⁶)—C(R⁶)₂, N═C(R⁶)or N(R⁶)—N(R⁶).

Embodiments of the present invention also include those wherein J is abond, V is a bond and Z is Z1 such that the following structure forms:

Embodiments of the present invention also include those wherein J is abond, V is a bond, Z is Z1 and T is —C(═O)—, such that the followingstructure forms:

Embodiments of the present invention also include those wherein J is abond and Z is Z1 such that the following structure forms:

Embodiments of the present invention also include those wherein V is abond and Z is Z1 such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isN, and Z is Z2 such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isN—C(R⁶)₂, and Z is Z2 such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isC═C(R⁶), and Z is Z2 such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isC═N, and Z is Z2, such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isN—C(R⁶)₂—C(R⁶)₂, and Z is Z2 such that the following structure forms:

Embodiments of the present invention also include those wherein J is abond, V is a bond, Z is Z1, Q is —N(R^(7a))—, and T is —C(═O)—, suchthat the following structure forms:

Embodiments of the present invention also include those wherein J is abond, V is a bond, Z is Z1, Q is —C(R^(7a))₂—, and T is —C(═O)—, suchthat the following structure forms:

Embodiments of the present invention also include those wherein J is abond, V is a bond, Z is Z1, Q is —N═, and T is ═C(R^(7b))—, such thatthe following structure forms:

Embodiments of the present invention also include those wherein J is abond, V is a bond, Z is Z1, Q is —C(R^(7a))₂—, and T is —C(R^(7b))₂—,such that the following structure forms:

Embodiments of the present invention also include those wherein J is abond, V is a bond, Z is Z1, Q is —C(R^(7a))═, T is ═C(R^(7b))—, and theatoms to which R^(7a) and R^(7b) are attached are joined together toform a benzene, pyridine, or diazine ring such that one of the followingstructures form:

Embodiments of the present invention also include those wherein J is abond, V is C(R⁶)₂, Z is Z1, Q is —C(R^(7a))═, T is ═C(R^(7b))—, and theatoms to which R^(7a) and R^(7b) are attached are joined together toform a benzene, or pyridine ring such that one the following structuresform:

Embodiments of the present invention also include those wherein J is O,V is a bond, Z is Z1, Q is —C(R^(7a))═, T is ═C(R^(7b))—, and the atomsto which R^(7a) and R^(7b) are attached are joined together to form abenzene, or pyridine ring such that one of the following structuresform:

Embodiments of the present invention also include those wherein G-L isN, Z is Z2, Q is —C(R^(7a))₂—, and T is —C(R^(7b))₂—, such that thefollowing structure forms:

Embodiments of the present invention also include those wherein G-L isN, Z is Z2, Q is —C(R^(7a))═ and T is ═C(R^(7b))— such that thefollowing structure forms:

Embodiments of the present invention also include those wherein G-L isN, Z is Z2, Q is —N═, and T is ═C(R^(7b))—, such that the followingstructure forms:

Embodiments of the present invention also include those wherein G-L isN, Z is Z2, Q is —C(R^(7a))₂—, and T is —C(O)—, such that the followingstructure forms:

Embodiments of the present invention also include those wherein G-L isC═C(R⁶), Z is Z2, Q is —C(R^(7a))═ and T is ═C(R^(7b))—, such that thefollowing structure forms:

Embodiments of the present invention also include those wherein G-L isC═C(R⁶), Z is Z2, Q is —C(R^(7a))═ and T is ═N—, such that the followingstructure forms:

Embodiments of the present invention also include those wherein G-L isC═C(R⁶), Z is Z2, Q is —N═ and T is ═C(R^(7b))—, such that the followingstructure forms:

Embodiments of the present invention also include those wherein G-L isC═N, Z is Z2, Q is —C(R^(7a))═ and T is ═C(R^(7b))—, such that thefollowing structure forms:

Embodiments of the present invention also include those wherein G-L isN, Z is Z2, Q is —C(R^(7a))═, and T is ═C(R^(7b))—, and the atoms towhich R^(7a) and R^(7b) are attached are joined together to form abenzene, pyridine, or diazine ring such that one of the followingstructures form:

Embodiments of the present invention also include those wherein G-L isN—C(R⁶)₂, Z is Z2, Q is —C(R^(7a))═, and T is ═C(R^(7b))—, and the atomsto which R^(7a) and R^(7b) are attached are joined together to form abenzene, or pyridine ring such that one of the following structuresform:

Embodiments of the present invention also include those wherein G-J isC═N, Z is Z2, Q is —C(R^(7a))═, and T is ═C(R^(7b))—, and the atoms towhich R^(7a) and R^(7b) are attached are joined together to form abenzene ring such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isC═C(R⁶), Z is Z2, Q is —C(R^(7a))═, and T is ═C(R^(7b))—, and the atomsto which R^(7a) and R^(7b) are attached are joined together to form abenzene ring such that the following structure forms:

Embodiments of the present invention also include those wherein G-L isN—C(R⁶)₂—C(R⁶)₂, Z is Z2, Q is —C(R^(7a))═, and T is ═C(R^(7b))—, andthe atoms to which R^(7a) and R^(7b) are attached are joined together toform a benzene ring such that the following structure forms:

In embodiments where M is a bond, K is a bond, J is a bond, V is a bond,Q is —C(R^(7a))═, and T is ═C(R^(7b))—, and the atoms to which R^(7a)and R^(7b) are attached are joined together to form a phenyl orpyridinyl ring, the following structures form:

In embodiments where M is a bond, K is CH₂, J is NR⁶ where R⁶ isselected from —CH₃ and H, V and Q are each bonds and T is ═C(O)—, thefollowing structures form:

In embodiments where M is a bond, K is a bond, J is a bond, V is a NR⁶where R⁶ is H, and Q and T are each bonds, the following structureforms:

In embodiments where M is —NH—, K is CH₂, J is NR⁶ where R⁶ is H, V andQ are each bonds and T is ═C(O)—, the following structure forms:

In embodiments where M is —NH—, K is a bond, J is a bond, V is a bond, Tis —C(O)— and Q is NR^(7a) where R^(7a) is H, the following structureforms:

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, R² is recited four times informula I, and each R² in formula I may independently be any of thesubstructures defined under R². The invention is not limited tostructures and substructures wherein each R² must be the same for agiven structure. The same is true with respect to any variable appearingmultiple time in a structure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R¹⁰and R¹¹ substituents are capable of forming a ring structure. Moreover,even those substituents capable of ring formation may or may not form aring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no double or triple bonds. Thus C₁₋₆alkyl is definedto identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linearor branched arrangement, such that C₁₋₆alkyl specifically includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which forms aring of three or more atoms. C₀ or C₀alkyl is defined to identify thepresence of a direct covalent bond.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. Thus C₂₋₆alkynyl is defined to identifythe group as having 2, 3, 4, 5 or 6 carbons in a linear or branchedarrangement, such that C₂₋₆alkynyl specifically includes 2-hexynyl and2-pentynyl.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronaphthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 5- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazolidinone,imidazoline, imidazolinone, indoline, isochroman, isoindoline,isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine,morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane,2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The number of certain variables present in certain instances is definedin terms of the number of carbons present. For example, variable “p” isoccasionally defined as follows: “p is 0 to 2q+1, for a substituent withq carbons”. Where the substituent is “(F)_(p)C₁₋₃ alkyl” this means thatwhen there is one carbon, there are 2(1)+1=3 fluorines. When there aretwo carbons, there are 2(2)+1=5 fluorines, and when there are threecarbons there are 2(3)=1=7 fluorines.

The terms “bond” and “absent” are in certain instances herein usedinterchangeably to refer to an atom (or chemical moiety) which is notpresent in a particular embodiment of the invention. In suchembodiments, the atoms adjacent the “bond” or “absent” atom are simplybonded to one another. For example, in certain embodiments of theinvention described and claimed herein, where variable “J” is defined asa bond the adjacent —C(O) moiety is bonded directly to the position 4carbon of the piperidine. The absence of a specific atom or moiety,particularly an atom or moiety which serves to link or connect otheratoms or moieties, does not imply that such other atoms or moieties arenot linked.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly,membranes (25 μg) were incubated in 1 ml of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 μM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 μl) was addedand the radioactivity was counted on a Topcount (Packard instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochem. Pharmacol. 22, 3099-3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimalessential medium (MEM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/ml penicillin and 100 μg/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-Dlysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 μM isobutylmethylxanthine inserum-free MEM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 15 min, then the cells were washed with PBSand processed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 mM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIEShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′PmeI fragment. Human RAMP1 (Genbank accession numberAJ001014) was subcloned into the expression vector pIRESpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLRand RAMP1 expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were diluted andselective medium (growth medium+300 ug/ml hygromycin and 1 ug/mlpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/mil hygromycin and 0.5ug/mil puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCRLR/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:

$Y_{obsd} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\%\mspace{14mu} I_{\max}} - {\%_{Imin}/100}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\mspace{14mu}{I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$Where Y is observed CPM bound, Y_(max) is total bound counts, Y min isnon specific bound counts, (Y max−Y min) is specific bound counts, % Imax is the maximum percent inhibition, % I min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human α-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K₁ or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-migraine agent, such as ergotamine and dihydroergotainine, or otherserotonin agonists, especially a 5-HT_(1B/1D) agonist, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such asPNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenaseinhibitor, such as a selective cyclooxygenase-2 inhibitor, for examplerofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; anon-steroidal anti-inflammatory agent or a cytokine-suppressinganti-inflammatory agent, for example with a compound such as ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly,the instant compounds may be administered with an analgesic such asaspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone,acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; a renin inhibitor; a granzyme Binhibitor; a substance P antagonist; an endothelin antagonist; anorepinephrin precursor; anti-anxiety agents such as diazepam,alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptorantagonists; opiod agonists such as codeine, hydrocodone, tramadol,dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; an antidepressant, for exampleamitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine,doxepin, protriptyline, desipramine, trimipramine, or imipramine; aleukotriene antagonist, for example montelukast or zafirlukast; aninhibitor of nitric oxide or an inhibitor of the synthesis of nitricoxide.

Also, the present compounds may be used in conjunction with gap junctioninhibitors; neuronal calcium channel blockers such as civamide; AMPA/KAantagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergotalkaloids other than ergotamine and dihydroergotamine, for exampleergonovine, ergonovine, methylergonovine, metergoline, ergoloidmesylates, dihydroergocomine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocomine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol,metoprolol or nadolol, and the like; a MAO inhibitor, for examplephenelzine; a calcium channel blocker, for example flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, or prochlorperazine; neurolepticssuch as olanzapine, droperidol, prochlorperazine, chlorpromazine andquetiapine; an anticonvulsant such as topiramate, zonisamide,tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine,gabapentin, pregabalin or divalproex sodium; an anti-hypertensive suchas an angiotensin II antagonist, for example losartan, irbesartin,valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartanand candesartan cilexetil, an angiotensin I antagonist, an angiotensinconverting enzyme inhibitor such as lisinopril, enalapril, captopril,benazepril, quinapril, perindopril, ramipril and trandolapril; orbotulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as caramiphen, carbetapentane, or dextromethorphan;a diuretic; a prokinetic agent such as metoclopramide or domperidone; asedating or non-sedating antihistamine such as acrivastine, azatadine,bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine,phenylpropanolamine, or pseudoephedrine. The present compounds also maybe used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: ergotamine ordihydroergotamine; a 5-HT₁ agonist, especially a 5-HT_(1B/1D) agonist,in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, andother serotonin agonists; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the compound of the presentinvention to the other active ingredient(s) may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with another agent, the weightratio of the compound of the present invention to the other agent willgenerally range from about 1000:1 to about 1:1000, or from about 200:1to about 1:200. Combinations of a compound of the present invention andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, solutions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. Oral tablets may also be formulated for immediate release, suchas fast melt tablets or wafers, rapid dissolve tablets or fast dissolvefilms.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions are may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 7 milligrams to about350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes. The synthesis of intermediates and finalcompounds may be conducted as described in Schemes 1-10.

REACTION SCHEMES

The preparation of final compounds proceeds through intermediates suchas those of formula I and formula V, and the synthesis of eachintermediate is described herein.

In general, intermediates of the formulas I and V can be coupled througha urea linkage as shown in Scheme 1. The resulting amine afterdeprotection of 1 can be converted to a reactive carbamate, for examplep-nitrophenylcarbamate 2, which is subsequently reacted with an aminelike that of intermediate 3 to produce urea 4. Other activatedintermediates known to those skilled in the art can be used to preparecompounds like 4. For example, the resultant primary amine afterdeprotection of 1 can be directly acylated with the appropriatecarbamoyl chloride.

Intermediates of formula I can be prepared according to methodsdescribed in R. Freidinger et al, EP 0523846A2 (1993); M. G. Bock et al,J. Med. Chem. 1988, 31(1), 176-181; M. G. Bock et al, Bioorg. Med. Chem.Lett., 1994, 2(9), 987-998; A. Showell et al, Bioorg. Med. Chem. Lett.,1995, 5(24), 3023-3026; J. B. Hester Jr. et al, J. Med. Chem. 1980, 23,643-647; M. Gerecke et al, U.S. Pat. No. 4,346,031 (1982); A. Wasler etal, U.S. Pat. No. 4,280,957 (1981); and references cited therein.

The synthesis of compounds represented by intermediate formula V can beaccomplished by procedures similar to those described in Henning et al.,J. Med. Chem., 1987, 30, 814-819; Carpino et al., WO 96/35713; Brown etal., J. Chem. Soc. 1957, 682-686; Barlin et al., Aust. J. Chem. 1982, 35(11), 2299-2306; and references cited therein.

Additionally, the synthesis of compounds represented by intermediateformula V can be accomplished according to Schemes 2-10. For example, adiamino heterocycle, such as 2,3-diaminopyridine 5, can be reductivelyalkylated with ketones such as 6 to give the monoalkylated product 7(Scheme 2). Ring closure with carbonyldiimidazole furnishes imidazolone8. Final deprotection under standard conditions gives the intermediate3.

Triazolinones can be prepared according to Scheme 3. For example, a4-piperidinone 9 can be reductively aminated with a carbazate which,after reduction of hydrazone 10, gives the monoalkylated product 11.Deprotection to afford hydrazine 12 and condensation/ring closure with abenzothioyl carbamate such as 13 furnishes triazolinone 14. Finaldeprotection under standard conditions gives the product 15.

The intermediate 21 can be prepared according to the general methoddescribed by Takai et al., Chem. Pharm. Bull. 1985, 33, 1116-1128illustrated in Scheme 4.

A similar synthetic strategy can be used to construct the relatedbenzodiazepinone of formula 29 shown in Scheme 5. The starting alcohols22 are commercially available, or prepared according to procedures knownto those skilled in the art. Alcohol 22 can be converted to a halideusing standard conditions, such as triphenylphosphine and bromine toprepare the bromide 23. The halide is displaced with azide nucleophile,and the azide 24 reduced under standard conditions to give the primaryamine 25. This amine can be reductively alkylated with a suitablyprotected 4-piperidinone to give compound 26. Reduction of the nitrogroup is easily accomplished using a variety of conditions, andsubsequent cyclization can be achieved with carbonyldiimidazole toafford cyclic urea 28. Deprotection then liberates amine 29.

Quinolone 34 can be prepared by reaction of the anion derived from2-chloroquinoline and lithium diisopropylamide, with piperidone 31(Scheme 6). Concommitant elimination of the tertiary alcohol andhydrolysis of the chloroquinoline is accomplished with aqueoushydrochloric acid. Removal of the piperidine N-benzyl protective groupby catalytic hydrogenation also reduces the olefin formed in theprevious step and results in amine 34.

7-Azaindole (35) may be protected with a variety of protecting groups,such as the (trimethylsilyl)ethoxymethyl group shown in Scheme 7.Following the method of Marfat and Carter (Tetrahedron Lett., 1987, 28,4027-4030), treatment of 36 with pyridine hydrobromide perbromideprovides the dibromoazaoxindole 37, which may be reduced to thecorresponding azaoxindole 38 by reaction with zinc. The key alkylationof 38 with methyl 1,2-bis(bromomethyl)-4-benzoate (39) is carried outusing cesium carbonate in DMF to afford the spiroazaoxindole 40. Avariety of other bases and solvents may be employed in this alkylationreaction, and use of an alternative alkylating agent to the dibromideshown here can lead to different products. Removal of the SEM protectinggroup under standard conditions followed by saponification provides theacid intermediate 42. The methodology shown in Scheme 7 is not limitedto azaoxindoles such as 38, but may be applied to a variety of suitablyprotected heterocyclic systems to give the corresponding spirocompounds.

Alkylation of azaoxindole 38 with cis-1,4-dichloro-2-butene is carriedout using cesium carbonate in DMF to afford the spiroazaoxindole 43(Scheme 8). Removal of the SEM protecting group under standardconditions followed by osmium tetroxide catalyzed dihydroxylationprovides the diol intermediate 45. Periodate oxidative cleavage of thediol, followed by a double reductive amination (Org. Lett., 2000, 26,4205-4208) affords the spiropiperidine 46. The methodology shown inScheme 8 is not limited to azaoxindoles such as 38, but may be appliedto a variety of suitably protected heterocyclic systems to give thecorresponding spiro compounds.

The synthesis of the related spiropyridobenzoxazinone can beaccomplished according to Scheme 9. 2-Amino-6-chloropyridine 47 can beprotected as its Boc derivative under the action of sodiumhexamethyldisilazide and di-tert-butyl dicarbonate. Ortho metalationunder the conditions of Davies (Tetrahedron Lett., 2004, 45, 1721-1724)and addition of the resultant anion toN-benzyloxycarbonyl-4-piperidinone, gives after in situ cyclizationproduct 50. Final deprotection and dechlorination under standardhydrogenolysis conditions gives the intermediate 51.

In Scheme 10, Wittig reaction of the 4-ketopiperidine 49 gives theα,β-unsaturated ester 52. The resulting product can be isomerized to theβ,γ-unsaturated ester 53 under basic conditions (Tetrahedron Lett, 2004,4401-4404). Trimethylaluminum mediated amidation with2-amino-3-bromopyridine followed by amide alkylation with2-(trimethylsilyl)ethoxymethyl chloride affords the product 55. The keypalladium-mediated spirocyclization can be affected through the Fumodification (J. Amer. Chem. Soc., 2001, 6989-7000) of the Heckreaction. A two-stage deprotection with concomitant double bondreduction under standard conditions gives the desiredspironaphthyridinone 57.

Simple modifications of these routes, including different protectinggroup strategies, application of well-precedented methodology, and theuse of starting materials and reagents other than those described in theforegoing schemes, may be used to provide other intermediates ofinterest.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

INTERMEDIATES AND EXAMPLES

The following examples are provided so that the invention might be morefully understood. These examples are illustrative only and should not beconstrued as limiting the invention in any way.

Intermediate 1

2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridineDihydrochloride Step A.2-Amino-3-[(1-tert-butoxycarbonylpiperidin-4-yl)amino)pyridine

Sodium triacetoxyborohydride (14.5 g, 68.7 mmol) was added to a solutionof 2,3-diaminopyridine (5.00 g, 45.8 mmol) andN-(tert-butoxycarbonyl)-4-piperidone (9.58 g, 48.1 mmol) indichloroethane (75 mL) at room temperature. After 5 h, additional sodiumtriacetoxyborohydride was added (1.8 g) and again after another 2.5 h.The reaction was stirred overnight, and quenched with 5% aqueous sodiumhydroxide. This was extracted with methylene chloride, and washed with5% aqueous sodium hydroxide, water and saturated sodium chloridesolution. After drying over sodium sulfate, the solution was filteredand evaporated to give the crude product. This was purified bychromatography (silica gel, 3 to 5% methanol in methylene chloridegradient elution), which gave the title compound (4.44 g). MS: m/z=293(M+1) ¹H NMR (500 MHz, CD₃OD) δ 7.32 (dd, J=5, 1 Hz, 1H), 6.85 (dd, J=8,1 Hz, 1H), 6.59 (dd, J=8, 5 Hz, 1H), 4.04 (d, J=13 Hz, 2H), 3.46 (m,1H), 2.98 (br s, 2H), 2.01 (dd, J=12, 2 Hz, 2H), 1.46 (s, 9H), 1.37 (qd,J=12, 4 Hz, 2H).

Step B.2-Oxo-1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

Carbonyldiimidazole (0.70 g, 4.33 mmol) was added to a solution of2-amino-3-[(1-tert-butoxycarbonylpiperidin-4-yl)amino]pyridine (1.15 g,3.93 mmol) in acetonitrile (150 mL) at room temperature. After severalhours, an additional amount of carbonyldiimidazole was added (0.81 g),and the reaction stirred overnight. The acetonitrile was evaporated invacuo, the residue partitioned between water and chloroform, and theorganic phase washed with saturated brine and dried over magnesiumsulfate. The crude product was purified by chromatography (silica gel,1.2 to 2.5% methanol in methylene chloride gradient elution), which gavethe title compound (1.09 g). ¹H NMR (500 MHz, CDCl₃) δ 9.39 (br s, 1H),8.04 (dd, J=5, 1 Hz, 1H), 7.33 (dd, J=8, 1 Hz, 1H), 6.99 (dd, J=8, 5 Hz,1H), 4.50 (m, 1H), 4.32 (br s, 2H), 2.86 (br s, 2H), 2.20 (m, 2H), 1.86(d, J=12 Hz, 2H), 1.50 (s, 9H).

Step C. 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridineDihydrochloride

2-Oxo-1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine(1.03 g, 3.23 mmol) was dissolved in methanol (25 mL) and a solution of2 N hydrochloric acid in ether (8 mL) was added at room temperature.After 2 h, the volatiles were removed in vacuo, to give the titlecompound (0.92 g). MS: m/z=219 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 8.01(dd, J=6, 1 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=8, 6 Hz, 1H),4.60 (m, 1H), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq,J=13, 4 Hz, 2H), 2.12 (d, J=13 Hz, 2H).

Intermediate 2

4-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonylChloride

Phosgene (20% wt. in toluene; 1.8 mL, 3.43 mmol) was added to asuspension of2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumdichloride (100 mg, 0.343 mmol) and 2,6-lutidine (0.50 mL, 4.293 mmol)in dichloromethane (5 mL) at 0° C. After 2 h, the solution was added tosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with water (2×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Dichloromethane (10mL) was added, and the mixture was filtered to give the title compoundas a solid (48 mg). MS: m/z=281 (M+1). ¹H NMR (500 MHz, (CD₃)₂SO) δ11.58 (s, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.01-6.99(m, 1H), 4.52-4.46 (m, 1H), 4.31-4.23 (m, 2H), 3.38-3.33 (m, 1H),3.19-3.14 (m, 1H), 2.32-2.24 (m, 2H), 1.84-1.81 (m, 2H).

Intermediate 3

7-Piperidin-4-yl-7,9-dihydro-8H-purin-8-one Hydrochloride Step A.4-Amino-5-[(1-tert-butoxycarbonylpiperidin-4-yl)amino)pyrimidine

A mixture of 4,5-diaminopyrimidine (1.0 g, 9.1 mmol),N-(tert-butoxycarbonyl)-4-piperidone (3.0 g, 15 mmol) and sodiumtriacetoxyborohydride (1.2 g, 5.6 mmol) in dichloroethane (60 mL) wasstirred at room temperature for 3 d. The reaction was partitionedbetween chloroform (200 mL) and 3 N sodium hydroxide (30 mL). Afterdrying over magnesium sulfate, the organic phase was concentrated togive the title compound as a tan gum. MS: m/z=294 (M+1)

Step B. 7-(1-Benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one

The crude product from Step A,4-amino-5-[(1-tert-butoxycarbonylpiperidin-4-yl)amino)pyrimidine, wasrefluxed with carbonyldiimidazole (3.0 g, 18 mmol) in tetrahydrofuran(250 mL) for 2 d, cooled and concentrated. The crude product wasdissolved in ethyl acetate (25-50 mL), which in four crops gave thetitle compound as a white crystalline solid (1.3 g). MS: m/z=320 (M+1)

Step C. 7-Piperidin-4-yl-7,9-dihydro-8H-purin-8-one Hydrochloride

A mixture of 7-(1-benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (1.2g, 3.7 mmol) in 4 N hydrogen chloride in dioxane (50 mL), was stirredvigorously at room temperature for 3 h. The reaction was concentrated invacuo to give the title compound as a white solid. MS: m/z=220 (M+1)

Intermediate 4

4-Fluoro-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridineStep A. N-(5-Fluoropyridin-2-yl)-2,2-dimethylpropanamide

To a 0° C. solution of 2-amino-5-fluoropyridine (1.00 g, 8.92 mmol) andtriethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was addedtrimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89mmol). The solution was allowed to warm to room temperature. After 4 h,saturated aqueous NaHCO₃ was added, the layers separated and the aqueousphase backwashed with DCM. The combined organics were dried overmagnesium sulfate, filtered and concentrated and the residue purified bysilica gel chromatography (5%→40% EtOAc/hexanes) to give the titlecompound (1.34 g). MS: m/z=197.3 (M+1).

Step B. N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide

To a −78° C. solution ofN-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) intetrahydrofuran (25 μL) was added tert-butyllithium (1.31 mL of a 1.7 Msolution, 20.5 mmol) dropwise. After 3 h at −78° C.,4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at thereaction was allowed to warm to room temperature. After 1 h, saturatedaqueous NH₄Cl was added, and the tetrahydrofuran was removed via rotaryevaporator. Dichloromethane was added, the layers separated and theaqueous phase backwashed with DCM. The combined organics were dried overmagnesium sulfate, filtered and concentrated and the residue purified bytwo successive silica gel chromatographies (10%→80% EtOAc/hexanes, then5%→42% EtOAc/hexanes) to give the title compound (0.275 g). MS:m/z=234.0 (M+1).

Step C. 3-Azido-5-fluoropyridin-2-amine

N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (275 mg, 1.16mmol) in 3 N HCl (5 mL) was heated to 100° C. After 2 h, the volatileswere removed in vacuo, to give the title compound as its HCl salt (180mg). MS: m/z=154.2 (M+1).

Step D. 5-Fluoropyridine-2,3-diamine

The HCl salt of 3-azido-5-fluoropyridin-2-amine (1.90 g, 10.0 mmol) wasdissolved in tetrahydrofuran (100 mL) and treated with MP-Carbonate(Argonaut, 11.5 g). After 1 h, the mixture was filtered, rinsed withmore tetrahydrofuran, and concentrated. This residue was dissolved inethanol (50 mL), purged with argon, and 10% palladium on carbon wasadded (0.15 g). Hydrogen was introduced (1 atm) and the reaction stirreduntil complete. The catalyst was filtered and the solvent evaporatedfrom the filtrate to give the title compound (1.18 g). MS: m/z=128.0(M+1)

Step E. tert-Butyl4-[(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate

Sodium triacetoxyborohydride (2.95 g, 13.9 mmol) was added to a solutionof 5-fluoropyridine-2,3-diamine (1.18 g, 9.28 mmol), acetic acid (0.56g, 9.28 mmol) and I-(t-butoxycarbonyl)-4-piperidone (1.85 g, 9.28 mmol)in 1,2-dichloroethane (20 mL) at room temperature. After 1 h, thereaction was quenched with water (20 mL) and extracted withdichloromethane. After drying over sodium sulfate, the solution wasfiltered and evaporated to give the crude product. This was purified bychromatography, (silica gel, 5%→15% MeOH/DCM; then C-18, 95%water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)to give the title compound (0.73 g). MS: m/z=311.2 (M+1).

Step F. tert-Butyl4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

Carbonyldiimidazole (1.53 g, 9.41 mmol) was added to a solution oftert-butyl4-[(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate (0.73 g,2.35 mmol) in acetonitrile (10 mL) at room temperature. The reaction wasstirred until all the starting material was consumed (approximately 2 h)and then the solvent was evaporated in vacuo. The residue was dilutedwith water, extracted with dichloromethane (3×), dried over magnesiumsulfate and then concentrated. The crude product was purified bychromatography (silica gel, 1% to 10% methanol in methylene chloridegradient elution), which gave the title compound (0.309 g). MS:m/z=337.2 (M+1)

Step G.4-Fluoro-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

tert-Butyl4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate(340 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) andtrifluoroacetic acid (5 mL) was added. After 2 h, the reaction wasconcentrated, diluted with dichloromethane (5 mL) and a solution of 1 Nhydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature.Concentration afforded the title compound (302 mg). MS: m/z=237.2 (M+1)¹H NMR (500 MHz, CD₃OD) δ 7.92 (br s, 1H), 7.70 (dd, 1H), 4.60 (m, 1H),3.60 (s, 2H), 3.25 (dd, 2H), 2.70 (m, 2H), 2.10 (d, 2H).

Intermediate 5

3-(4-Piperidinyl)-3,4-dihydroquinazolin-2(1H)-one Hydrochloride

The title compound was prepared according to the procedure described byH. Takai et al., in Chem. Pharm. Bulletin 1985, 33(3) 1116-1128. ¹H NMR(500 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.79 (br s, 1H), 8.58 (br s, 1H),7.13 (t, J=8 Hz, 2H), 6.88 (t, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 4.37(tt, J=12, 4 Hz, 1H), 4.29 (s, 2H), 3.00 (q, J=11 Hz, 2H), 2.06 (dq,J=4, 12 Hz, 2H), 1.73 (d, J=12 Hz, 2H).

Intermediate 6

5-Phenyl-1-piperidin-4-yl-2,4-dihydro-3H-1,2,4-triazol-3-oneHydrochloride Step A: 9H-Fluoren-9-ylmethyl4-[(t-butoxycarbonyl)hydrazono]piperidine-1-carboxylate

A solution of 1-[(9H-fluoren-9-yl)methyloxycarbonyl]-4-piperidone (16.0g, 50.0 mmol) and tert-butyl carbazate 7.25 g, 55.5 mmol) in ethanol(250 mL) was refluxed for 1 h. The solution was cooled and concentrated.Addition of ether (100 mL) produced the title compound as a whiteprecipitate (21.0 g). ¹H NMR (500 MHz, CDCl₃) δ 7.77 (d, J=7 Hz, 2H),7.57 (d, J=7 Hz, 2H), 7.40 (t, J=7 Hz, 2H), 7.32 (t, J=7 Hz, 2H), 4.50(br s, 2H), 4.24 (t, J=6 Hz, 1H), 3.4-3.7 (br m, 4H), 2.47 (br s, 2H),2.2-2.1 (br m, 2H), 1.56 (s, 9H).

Step B: 9H-Fluoren-9-ylmethyl4-[(t-butoxycarbonyl)hydrazino]piperidine-1-carboxylate

A solution of 9H-fluoren-9-ylmethyl4-[(t-butoxycarbonyl)hydrazono]piperidine-1-carboxylate (10.0 g, 22.9mmol) in acetic acid (150 mL) was shaken with platinum oxide (1.0 g)under 45 psi hydrogen on a Parr apparatus for 2 h. The solution wasfiltered and concentrated to give the title compound.

Step C: 9H-Fluoren-9-ylmethyl 4-hydrazinopiperidine-1-carboxylate

A solution of 9H-fluoren-9-ylmethyl4-[(tert-butoxycarbonyl)hydrazino]piperidine-1-carboxylate (20 g, 45.7mmol) was dissolved in trifluoroacetic acid (100 mL) and stirred at roomtemperature for 1.5 h. The reaction was concentrated and the residuedissolved in methanol and purified by reverse phase HPLC. Pure fractionswere isolated and combined to give the trifluoroacetic acid salt of thetitle compound (3.01 g). ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J=8 Hz,2H), 7.61 (d, J=8 Hz, 2H), 7.40 (t, J=8 Hz, 2H), 7.32 (t, J=8 Hz, 2H),4.33 (d, J=6 Hz, 2H), 4.25 (t, J=6 Hz, 1H), 4.0-3.5 (br s, 6H), 3.05 (brs, 1H), 2.80 (br s, 2H), 1.89 (br s, 2H), 1.2 (br s, 2H).

Step D: 9H-Fluoren-9-ylmethyl4-(5-oxo-3-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate

A solution of 9H-fluoren-9-ylmethyl 4-hydrazinopiperidine-1-carboxylatetrifluoroacetic acid salt (2.95 g, 6.54 mmol) was refluxed for 2 h withethyl N-benzothioyl carbamate (1.50 g, 7.1 mmol) (prepared by theprocedure of E. P. Papadopoulus, J. Org. Chem., 1976, 41(6) 962-965) intetrahydrofuran (30 mL) with diisopropylethyl amine (1.25 mL, 7.1 mmol).The reaction was cooled and concentrated, then dissolved with heating inacetonitrile. A white solid crystallized upon cooling, giving the titlecompound (2.06 g). ¹H NMR (500 MHz, CDCl₃) δ 7.80 (d, J=7 Hz, 2H), 7.77(d, J=7 Hz, 2H), 7.61 (d, J=7 Hz, 2H), 7.48 (m, 3H), 7.40 (t, J=7 Hz,2H), 7.33 (t, J=7 Hz, 2H), 4.46 (d, J=6 Hz, 2H), 4.36 (m, 2H), 4.27 (t,J=6 Hz, 1H), 4.26 (br s, 1H), 3.02 (br s, 2H), 2.04 (br s, 2H), 1.94 (brm, 2H).

Step E: 5-Phenyl-1-piperidin-4-yl-2,4-dihydro-3H-1,2,4-triazol-3-oneHydrochloride

A solution of 9H-fluoren-9-ylmethyl4-(5-oxo-3-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate(2.06 g, 4.41 mmol) and diethylamine (15 mL) in tetrahydrofuran (15 mL)was stirred at room temperature for 2 h. The reaction was concentratedand the crude product purified by column chromatography (silica gel, 0to 10% {5% ammonium hydroxide/methanol} in dichloromethane gradientelution), giving the title compound as a white solid (0.95 g). ¹H NMR(500 MHz, CDCl₃) δ 7.84 (d, J=7 Hz, 2H), 7.47 (m, 3H), 4.30 (m, 1H),3.25 (d, J=13 Hz, 2H), 2.79 (t, J=13 Hz, 2H), 2.04 (d, J=4, 12 Hz, 2H),1.93 (br d, J=10 Hz, 2H).

Intermediate 7

3-(4-Piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-oneHydrochloride Step A. 2-(2-Bromoethyl)nitrobenzene

Triphenylphosphine (39.2 g, 0.150 mol) and carbon tetrabromide (49.5 g,0.150 mol) were added sequentially to a solution of2-(2-hydroxyethyl)-nitrobenzene (25.0 g, 0.150 mol) in methylenechloride (400 mL) at 0° C. The reaction was stirred overnight andquenched with saturated sodium bicarbonate solution. The methylenechloride phase was washed with saturated brine and dried over magnesiumsulfate. The crude product was treated with ethyl acetate, and theprecipitated triphenylphosphine oxide removed by filtration. Furtherpurification by flash chromatography by (silica gel, 0-10% ethyl acetatein hexane gradient elution) produced the title compound (27.9 g).

Step B. 2-(2-Azidoethyl)nitrobenzene

Sodium azide (22.8, 0.351 mol) in water (60 mL) was added to a solutionof 2-(2-bromoethyl)-nitrobenzene (27.9 g, 0.121 mol) in acetonitrile(120 mL). The reaction was refluxed for 4 h, cooled, and partitionedbetween methylene chloride and water. The organic phase was washed withsaturated brine, and dried over magnesium sulfate. The title compoundwas obtained as an oil (22.8 g).

Step C. 2-(2-Aminoethyl)nitrobenzene

Triphenylphosphine (31.1 g, 0.118 mol) and calcium carbonate (50 mg, 0.5mmol) were added to a solution of 2-(2-azidoethyl)nitrobenzene (22.8 g,0.118 mol) in benzene (500 mL). The reaction was stirred at roomtemperature until complete. The solvent was removed in vacuo, and theresidue treated with acetic acid (100 mL) and 48% hydrogen bromide (100mL) at 100° C. for 1 h. The reaction was cooled and concentrated. Waterwas added and the solution extracted with methylene chloride. Theaqueous layer was made basic by the addition of 5% aqueous sodiumhydroxide solution, then extracted with ethyl acetate. The organic phasewas washed with saturated brine and dried over sodium sulfate. The titlecompound was obtained as an oil (8.0 g). MS: m/z=167 (M+1).

Step D. t-Butyl4-{[2-(2-nitrophenyl)ethyl]amino}piperidine-1-carboxylate

A solution of 2-(2-aminoethyl)nitrobenzene (8.00 g, 48.1 mmol) and1-t-butoxycarbonyl-4-piperidinone (9.59 g, 48.1 mmol) in methanol (100mL) was brought to pH 5 by the addition of acetic acid. Sodiumcyanoborohydride (4.53 g, 72.2 mmol) was added and the reaction stirredfor 3 h. Methanol was removed in vacuo, and the residue partitionedbetween ethyl acetate and saturated sodium bicarbonate solution. Theorganic phase was washed with saturated brine and dried over sodiumsulfate. The title compound was obtained as an oil (19.27 g). MS:m/z=350 (M+1).

Step E. t-Butyl4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate

tert-Butyl 4-{[2-(2-nitrophenyl)ethyl]amino}piperidine-1-carboxylate and10% palladium on carbon (1.9 g) were stirred in ethanol (250 mL)overnight under one atmosphere hydrogen. Catalyst was filtered from thesolution and solvent removed in vacuo to provide the title compound(17.2 g). MS: m/z=320 (M+1)

Step F.3-(1-t-Butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-one

Carbonyldiimidazole (8.73 g, 53.8 mmol) was added to a solution oftert-butyl 4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate(17.2 g, 53.8 mmol) in dimethylformamide (200 mL), and stirred at roomtemperature for 2 h. The reaction was diluted with ethyl acetate andextracted with water, then saturated brine. The crude product waspurified by chromatography (silica gel, 0-30% ethyl acetate in methylenechloride gradient elution). The title compound was obtained as a darksolid (4.8 g).

Step G. 3-(4-Piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-oneHydrochloride

A solution of3-(1-t-butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazapin-2-one(4.80 g, 13.9 mmol) in ethyl acetate (300 mL) was saturated withhydrogen chloride gas at 0° C. The reaction was allowed to warm to roomtemperature and stirred overnight. The solid was filtered and washedwith ethyl acetate. The ethyl acetate filtrate was concentrated for asecond crop. The title compound was obtained as a solid (2.94 g). MS:m/z=246 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 7.10 (m, 2H), 6.94 (d, J=8 Hz,1H), 6.91 (t, J=8 Hz, 1H), 4.35 (tt, J=10, 1 Hz, 1H), 3.52 (m, 4H), 3.12(t, J=12 Hz, 2H), 3.05 (m, 2H), 2.07 (qd, J=12, 4 Hz, 2H), 1.99 (m, 2H).

Intermediate 8

3-(4-Piperidinyl)quinolin-2-(1H)-one Step A.3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline

A solution of n-butyllithium in hexane (1.6 M, 38.2 mL, 61.1 mmol) wasadded to a solution of diisopropylamine (8.6 mL, 61.1 mmol) intetrahydrofuran (140 mL) at −78° C. under argon. After 1 h, a solutionof 2-chloroquinoline (10.00 g, 61.1 mol) in tetrahydrofuran (30 mL) wasadded via syringe. After 1 h, a solution of 1-benzyl-4-piperidinone(11.3 mL, 61.1 mmol) was added, and the reaction stirred for anadditional 40 min at −78° C., then allowed to warm to room temperature.The reaction was cooled to −20° C. and quenched with water. The reactionsolution was extracted with ethyl acetate, and the organic phase washedwith saturated brine and dried over magnesium sulfate. Chromatographicpurification (silica gel, 0 to 10% {5% ammonium hydroxide/methanol} inmethylene chloride gradient elution) gave the title compound, 11.3 g.MS: m/z=353 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 1H), 8.00 (d, J=8Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.72 (dt, J=1, 10 Hz, 1H), 7.57 (dt,J=1.8 Hz, 1H), 7.39-7.26 (m, 5H), 3.61 (s, 2H), 2.85 (d, J=11 Hz, 2H),2.59 (t, J=12 Hz, 2H), 2.48 (dt, J=4, 13 Hz, 2H), 2.13 (d, J=12 Hz, 2H).

Step B. 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-(1H)-one

3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline (11.0 g, 31.1mmol) was refluxed in 6 N hydrochloric acid for 8 h. The solution wascooled and water (100 mL) added. The precipitated solid was collectedand dried to give the title compound, 7.9 g. MS: m/z=317 (M+1). ¹H NMR(500 MHz, CD₃OD) δ 7.97 (s, 1H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H),7.55 (m, 4H), 7.35 (d, J=9 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 6.50 (m, 1H),4.49 (ABq, J=13 Hz, Δν=16 Hz, 2H), 3.92 (m, 2H), 3.76 (dt, J=12.4 Hz,1H), 3.40 (m, 1H), 2.96 (m, 2H).

Step C. 3-(4-Piperidinyl)quinolin-2-(1H)-one

A solution of3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-(1H)-one (4.00 g,12.6 mmol) in methanol (500 mL) was degassed with argon, and 10%palladium on carbon (1.2 g) added. The reaction was placed under 1 atmhydrogen and heated to 50° C. for 5.5 h. The reaction was cooled andfiltered through celite. Concentration provided the title compound, 2.7g. MS: m/z=229 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 7.80 (s, 1H), 7.67 (d,J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (t, J=8Hz, 1H), 3.52 (t, J=12 Hz, 2H), 3.17 (dt, J=3, 13 Hz, 2H), 3.15 (m,overlaps with δ3.17 peak, 1H), 2.18 (d, J=14 Hz, 2H), 1.91 (dq, J=3, 12Hz, 2H).

Intermediate 9

1-Piperidin-4-ylimidazolidine-2,4-dione Step A: tert-Butyl4-[(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate

Sodium cyanoborohydride (189 mg, 3.01 mmol) was added to a solution of1-boc-4-piperidone (500 mg, 2.51 mmol) and glycine ethyl esterhydrochloride (350 mg, 2.51 mmol) in methanol (12.5 mL). After 16 h, themixture was quenched with saturated ammonium chloride solution,concentrated, and partitioned between dichloromethane and saturatedsodium bicarbonate solution. The organic layer was washed with brine,dried over magnesium sulfate, filtered, and concentrated. Purificationby silica gel chromatography [100% dichloromethane→95%dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the titlecompound (600 mg).

Step B: tert-Butyl4-(2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate

Potassium cyanate (31 mg, 0.384 mmol) was added to a solution oftert-butyl 4-[(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate (100mg, 0.384 mmol) in water (2 mL). Acetic acid was then added to adjust pHof reaction to 4-5 and the mixture was heated at 40° C. After 16 h, thereaction was cooled to ambient temperature and purified by reverse phaseHPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1%trifluoroacetic acid) to give the title compound (33 mg).

Step C: 1-Piperidin-4-ylimidazolidine-2,4-dione

Trifluoroacetic acid (0.300 mL) was added to a solution of tert-butyl4-(2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (32 mg, 0.113mmol) in dichloromethane (1 mL). After 4 h, the reaction wasconcentrated to give the title compound. MS: m/z=184.04 (M+1).

Intermediate 10

(±)-2′-Oxo-1,1′,2′,3-tetrahydrospiro[indene-23′-pyrrolo[2,3-b]pyridine]-5-carboxylicAcid Step A.1-{[2-Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) wasadded in portions over 25 min to a solution of 7-azaindole (39.8 g,0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h.2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was thenadded slowly over 15 min, keeping the temperature of the reactionmixture below 10° C. After 1 h, the reaction was quenched with H₂O (500mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered,concentrated and dried under high vacuum to give the title compound. MS:m/z=249 (M+1).

Step B.3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (43.1 g,0.174 mol) in dioxane (300 mL) was added dropwise over 30 min to asuspension of pyridine hydrobromide perbromide (277 g, 0.868 mol) indioxane (300 mL). The reaction was stirred at ambient temperature usingan overhead mechanical stirrer. After 60 min, the biphasic reactionmixture was quenched with H₂O (300 mL) and extracted with EtOAc. Theaqueous layer was washed with EtOAc (2×300 mL) and the combined organiclayers were washed with H₂O (4×300 mL; the final wash was pH 5-6), thenbrine (300 mL), then dried over MgSO₄, filtered and concentrated underreduced pressure. The crude product was immediately dissolved in CH₂Cl₂and the solution filtered through a plug of silica, eluting with CH₂Cl₂until the dark red color had completely eluted from the plug. Thefiltrate was washed with saturated aqueous NaHCO₃ (400 mL), then brine(400 mL), dried over MgSO₄ and concentrated in vacuo to give the titlecompound. MS: m/z=423 (M+1).

Step C.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(65 g, 0.154 mol) in THF (880 mL) and saturated aqueous ammoniumchloride (220 mL). After 3 h, the reaction was filtered and concentratedin vacuo. The residue was partitioned between EtOAc and H₂O whichresulted in the formation of a white precipitate. Both layers werefiltered through a Celite pad and the layers were separated. The aqueouslayer was washed with EtOAc (2×) and the combined organic layers werewashed with H₂O, dried over MgSO₄, filtered, and concentrated. The crudeproduct was filtered through a plug of silica gel eluting withCH₂Cl₂:EtOAc—90:10 and the eluant was concentrated under reducedpressure to provide the title compound. MS: m/z=265 (M+1).

Step D. (±)-Methyl2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate

To a solution of methyl 1,2-bis(bromomethyl)-4-benzoate (9.20 g, 28.6mmol) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(7.55 g, 28.6 mmol) in DMF (70 mL) was added cesium carbonate (9.78 g,30.0 mmol). After 4 h the reaction mixture was partitioned between Et₂O(100 mL) and H₂O (100 mL). The aqueous layer was extracted further withEt₂O (2×100 mL). The combined organic layers were washed with H₂O (2×100mL), then brine (100 mL), then dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—85:15to 70:30, to give the title compound. MS: m/z=425 (M+1).

Step E.(±)-2′-Oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylicAcid

To a solution of (±)-methyl2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate(3.65 g, 8.60 mmol) in CH₂Cl₂ (80 mL) was added CF₃CO₂H (40 mL, 52 mmol)and the resulting mixture was stirred at ambient temperature for 18 h,then concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (100 mL)and treated with ethylene diamine (2.3 mL, 34.4 mmol). The reactionmixture was stirred at ambient temperature for 18 h, then diluted withsaturated aqueous NaHCO₃ (50 mL). The organic layer was removed and theaqueous layer was extracted further with CH₂Cl₂ (2×100 mL). The combinedorganic layers were washed with brine (50 mL), then dried over MgSO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with CH₂Cl₂:MeOH—97:3, to give methyl2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylateas a tan solid. This solid was dissolved in MeOH (22 mL) and 1 N sodiumhydroxide (25.4 mL, 25.4 mmol) was added. The reaction mixture washeated at 60° C. for 18 h then allowed to cool. The mixture wasacidified by addition of 6 N HCl, and the resulting precipitate wasisolated by filtration, washed with H₂O, and dried in vacuo to give thetitle compound as an off-white solid. MS: m/z=281 (M+1).

Intermediate 11

Spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one DihydrochlorideStep A. 1-{[2-Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) wasadded in portions over 25 min to a solution of 7-azaindole (39.8 g,0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h.2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was thenadded slowly over 15 min, keeping the temperature of the reactionmixture below 10° C. After 1 h, the reaction was quenched with H₂O (500mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered,concentrated and dried under high vacuum to give the title compound. MS:m/z=249 (M+1).

Step B.3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

A solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine from StepA (43.1 g, 0.174 mol) in dioxane (300 mL) was added dropwise over 30 minto a suspension of pyridine hydrobromide perbromide (277 g, 0.868 mol)in dioxane (300 mL). The reaction was stirred at ambient temperatureusing an overhead mechanical stirrer. After 60 min, the biphasicreaction mixture was quenched with H₂O (300 mL) and extracted withEtOAc. The aqueous layer was washed with EtOAc (2×300 mL) and thecombined organic layers were washed with H₂O (4×300 mL; the final washwas pH 5-6), then brine (300 mL), then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was immediatelydissolved in CH₂Cl₂ and the solution filtered through a plug of silica,eluting with CH₂Cl₂ until the dark red color had completely eluted fromthe plug. The filtrate was washed with saturated aqueous NaHCO₃ (400mL), then brine (400 mL), dried over MgSO₄ and concentrated in vacuo togive the title compound. MS: m/z=423 (M+1).

Step C.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-h]pyridin-2-onefrom Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueousammonium chloride (220 mL). After 3 h, the reaction was filtered andconcentrated in vacuo. The residue was partitioned between EtOAc and H₂Owhich resulted in the formation of a white precipitate. Both layers werefiltered through a Celite pad and the layers were separated. The aqueouslayer was washed with EtOAc (2×) and the combined organic layers werewashed with H₂O, dried over MgSO₄, filtered, and concentrated. The crudeproduct was filtered through a plug of silica gel eluting withCH₂Cl₂:EtOAc—90:10 and the eluant was concentrated under reducedpressure to provide the title compound. MS: m/z=265 (M+1).

Step D. spiro[cyclopent-3-ene-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of cis-1,4-dichloro-2-butene (1.98 g, 15.8 mmol) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(3.49 g, 13.2 mmol) in DMF (175 mL) was added cesium carbonate (10.7 g,32.9 mmol). After 24 h the reaction mixture was partitioned between Et₂O(200 mL) and H₂O (200 mL). The aqueous layer was extracted further withEt₂O (2×200 mL). The combined organic layers were washed with H₂O (2×100mL), then brine (100 mL), dried over MgSO₄, filtered, and concentratedunder reduced pressure. To a solution of this material indichloromethane (150 mL) was added trifluoroacetic acid (150 mL). After1 h, the reaction was concentrated, dissolved in EtOH (150 mL) and 2NHCl (150 mL) was added. This mixture was heated at 45° C. for 48 h. Themixture was concentrated, diluted with saturated aqueous NaHCO₃, andextracted with dichloromethane (2×). The combined organic layers weredried and concentrated. The crude product was purified by silica gelchromatography, eluting with a gradient of 0 to 5%methanol:dichloromethane to give the title compound (0.62 g). MS:m/z=187.1 (M+1).

Step E.3,4-dihydroxyspiro[cyclopentane-1,3′-pyrrolo[2,3-b]pyridin]-2′(1-one

To a mixture of trimethylamine-N-oxide dihydrate (408 mg, 3.67 mmol) andspiro[cyclopent-3-ene-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (622 mg,3.34 mmol) in dichloromethane (115 mL) was added osmium tetroxide (25 uLof 2.5% solution in 2-methyl-2-propanol). After 24 h the reactionmixture was concentrated. The crude product was loaded onto a silica gelchromatography column with a minimal amount of methanol and eluted witha gradient of 5 to 20% methanol:dichloromethane to give the titlecompound (0.63 g). MS: m/z=221.0 (M+1).

Step F. tert-butyl2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridine]-1-carboxylate

To a mixture of3,4-dihydroxyspiro[cyclopentane-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one(640 mg, 2.91 mmol) in 3:1 ethanol:water (160 mL) was added sodiumperiodate (622 mg, 2.91 mmol). Upon consumption of the startingmaterial, ammonium hydroxide (50 mL) was slowly added to the reactionmixture. Palladium hydroxide (200 mg, 20%) was added and the reactionwas hydrogenated at 50 psi. After 24 h, 200 mg of palladium hydroxidewas added and the hydrogenation continued for an additional 24 h. Thereaction mixture was filtered through celite and concentrated. Thismaterial was dissolved in DMF (10 mL) and di-tert-butyl dicarbonate (635mg, 2.91 mmol) was added followed by triethylamine (0.811 mL, 5.82mmol). After 24 h, the reaction was diluted with saturated aqueousNaHCO₃ and extracted with ether (3×). The combined organic layers werewashed with water (3×), dried and concentrated. The crude product waspurified by silica gel chromatography, eluting with a gradient of 0 to10% methanol:dichloromethane to give the title compound (489 mg). MS:m/z=304.1 (M+1).

Step G. Spiro[piperidine-4,3′-pyrrolo[2,3-h]pyridin]-2′(1′H)-oneDihydrochloride

tert-Butyl2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridine]-1-carboxylate(451 mg, 1.49 mmol) was dissolved in ethyl acetate (3 mL) and a solutionof 4N hydrochloric acid in dioxane (7.5 mmol) was added at roomtemperature. After 24 h, the volatiles were removed in vacuo, to givethe title compound (404 mg). MS: m/z=204.1 (M+1). ¹H NMR (500 MHz,CD₃OD) δ 8.31 (d, J=7.1 Hz, 1H), 8.20 (d, J=6.1 Hz, 1H), 7.45 (dd,J=6.8, 6.8 Hz, 1H), 3.74 (brdd, 2H), 3.47 (brdd, 2H), 2.35 (brddd, 2H),2.21 (brd, 2H).

Intermediate 12

Spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′)-one Step A.tert-Butyl (6-chloropyridin-2-yl)carbamate

To a solution of 2-amino-6-chloropyridine (5.24 g, 40.8 mmol) and sodiumhexamethyldisilazide (1.0 M, 89.8 mL, 89.8 mmol) in THF (35 mL) wasadded a solution of di-tert-butyl dicarbonate (9.80 g, 44.9 mmol) in THF(35 mL). After 24 h the reaction was concentrated and the residue waspartitioned between EtOAc (30 mL) and 1N HCl (100 mL). The aqueous layerwas extracted further with EtOAc (2×). The combined organic layers werewashed with NaHCO₃, dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of 20 to 100%dichloromethane:hexane to give the title compound (7.73 g). MS:m/z=173.0 (M−^(t)Bu).

Step B. Benzyl7′-chloro-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxylate

To a −20° C. solution of N,N,N′,N′-tetramethylethylenediamine (0.335 g,2.89 mmol) in THF (1 mL) was added n-butyllithium (2.5M, 1.15 mL, 2.89mmol) over 10 min. After 30 min, the mixture was cooled to −78° C. andtert-butyl (6-chloropyridin-2-yl)carbamate (0.300 g, 1.31 mmol) in THF(0.8 mL) was added over 15 min. After 1 h, the reaction was warmed to−50° C., stirred for 2 h and then N-benzyloxycarbonyl-4-piperidinone(0.459 g, 1.97 mmol) in THF (1 mL) was added over 10 min. The reactionwas allowed to warm to room temperature and then stirred for 24 h. Asolution of saturated aqueous NaHCO₃ was added and the mixture extractedwith EtOAc (3×). The combined organic layers were washed with H₂O,brine, dried over MgSO₄, filtered, and concentrated under reducedpressure. The crude product was purified by silica gel chromatography,eluting with a gradient of 25 to 50% ethyl acetate:hexane to give thetitle compound (0.160 g). MS: m/z=338.0 (M+1).

Step C. Spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one

10% Palladium on carbon (300 mg) was added to a solution of benzyl7′-chloro-2′-oxo-1′,2′-dihydro-1H-spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxylate(1.85 g, 1.77 mmol) in EtOH (250 mL). The reaction vessel was evacuatedand back-filled with nitrogen (3×), then back-filled with hydrogen (1atm). After 24 h, the mixture was filtered though celite andconcentrated to give the title compound (1.07 g). MS: m/z=220.1 (M+1).¹H NMR (500 MHz, CD₃OD) δ 8.26 (dd, J=1.7, 5.0 Hz, 1H), 7.69 (dd, J=1.6,7.7 Hz, 1H), 7.16 (dd, J=5.0, 7.7 Hz, 1H), 3.49-3.42 (m, 4H), 2.38-2.25(m, 4H).

Intermediate 13

1H-Spiro[1,8-naphthyridine-4,4′-piperidin]-2(3H)-one Step A. Benzyl4-(2-methoxy-2-oxoethlylidene)piperidine-1-carboxylate

A solution of N-benzyloxycarbonyl-4-piperidinone (5.0 g, 21.4 mol) andmethyl (triphenylphosphoranylidene)acetate (10.0 g, 30.0 mmol) inbenzene (100 mL) was heated at 75° C. for 48 h. The reaction wasconcentrated, diluted with ether, the precipitate filtered off, and therinsate concentrated. The crude product was purified by silica gelchromatography, eluting with a gradient of 20 to 60% ethylacetate:hexanes to give the title compound (5.25 g). MS: m/z=290.1(M+1).

Step B. Benzyl4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate

A solution of benzyl4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (5.25 g, 18.1 mol)and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.71 mL, 18.1 mol) in DMF (120mL) was stirred at room temperature. After 3 d the reaction was dilutedwith water and extracted with ether (4×). The organic washes werecombined, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was purified by silica gel chromatography,eluting with a gradient of 5 to 30% ethyl acetate:hexanes to give thetitle compound (2.44 g). MS: m/z=290.1 (M+1). ¹H NMR (500 MHz, CDCl₃) δ7.30-7.25 (m, 5H), 5.5 (brs, 1H), 5.2 (s, 2H), 4.0 (brs, 2H), 3.7 (s,3H), 3.6 (brs, 2H), 3.0 (s, 2H), 2.2 (brs, 2H).

Step C. Benzyl4-[2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate

Trimethylaluminum (2.0 M, 2.05 mL, 4.10 mol) was added slowly to a 0° C.solution of benzyl4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2B)-carboxylate (0.79 g,2.73 mol) and 2-amino-3-bromopyridine (0.520 g, 3.00 mmol) in1,2-dichloroethane (15 mL). After 30 min, the reaction was heated to 55°C. for 48 h. The reaction was quenched by the careful addition ofsaturated aqueous sodium bicarbonate and the mixture extracted withdichlormethane (4×). The combined organic layers were washed with 1Nsodium potassium tartrate, brine, dried over MgSO₄, filtered, andconcentrated. The crude product was purified by silica gelchromatography, eluting with a gradient of 50 to 100% ethylacetate:hexanes to give the title compound (2.44 g). MS: m/z=430.0(M+1).

Step D. Benzyl 4-[2-((3-bromopyridin-2-yl){[2-(trimethylsilyl)ethoxy]methyl}amino)-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate

Sodium hydride (60% dispersion in mineral oil; 117 mg, 4.88 mol) wasadded in portions over 10 min to a solution of benzyl4-{2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl}-3,6-dihydropyridine-1(2H)-carboxylate(1.91 g, 4.43 mol) in THF (15 mL) at 0° C. After 0.5 h,2-(trimethylsilyl)ethoxymethyl chloride (0.861 mL, 4.88 mol) was thenadded slowly, keeping the temperature of the reaction mixture below 10°C. After 4 h, sodium hydride (60 mg) and 2-(trimethylsilyl)ethoxymethylchloride (0.45 ml) were added and the reaction allowed to warm to roomtemperature overnight. The reaction was quenched with saturated aqueousammonium chloride and the mixture was extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The crude product was purified by silica gelchromatography, eluting with a gradient of 40 to 70% ethylacetate:hexanes to give the title compound (1.51 g). MS: m/z=560.2(M+1).

Step E. Benzyl2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate

To a mixture of N-methyldicyclohexylamine (0.042 mg, 0.20 mmol) andbenzyl 4-[2-((3-bromopyridin-2-yl){[2-(trimethylsilyl)ethoxy]methyl}amino)-2-oxoethyl]-3,6-dihydropyridine-1(2H)-carboxylate(100 mg, 0.178 mmol) in dioxane (2 mL) was addedbis(tri-tert-butylphosphine) palladium(0) (9 mg, 0.018 mmol). After 5min, the reaction was heated to 50° C. After 90 min,bis(tri-tert-butylphosphine) palladium(0) (9 mg) was added. After anadditional 30 min at 50° C., the reaction mixture was diluted with waterand extracted with ether (3×). The combined organic layers were driedover MgSO₄, filtered, and concentrated. The crude product was purifiedby silica gel chromatography, eluting with a gradient of 5 to 60% ethylacetate:hexanes to give the title compound (68 mg). MS: m/z=480.2 (M+1).

Step F. 1H-Spiro[1,8-naphthyridine-4,4′-piperidin]-2(3H)-one

To a mixture of benzyl2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate(384 mg, 0.800 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic acid (10 mL). After 3 h, the reaction was concentrated,diluted with dichloromethane (10 mL) and ethylenediamine (720 mg, 12.0mmol) was added. After 18 h, the reaction was concentrated, the residuepartitioned between saturated aqueous NaHCO₃ and dichloromethane, andthe layers separated. The aqueous phase was extracted with furtherportions of dichloromethane (2×), the organic layers combined, dried,and concentrated. 10% Palladium on carbon (300 mg) was added to asolution of this material in EtOH (10 mL). The reaction vessel wasevacuated and back-filled with nitrogen (3×), then back-filled withhydrogen (1 atm). After 24 h, the mixture was filtered though celite andconcentrated to give the title compound (130 mg). MS: m/z=218.1 (M+1).¹H NMR (500 MHz, CD₃OD) δ 8.14 (dd, J=1.6, 5.0 Hz, 1H), 7.80 (dd, J=1.6,7.7 Hz, 1H), 7.10 (dd, J=5.0, 7.7 Hz, 1H), 2.98-2.95 (m, 4H), 2.78 (s,2H), 1.96-1.90 (m, 2H), 1.69 (brd, J=11.5 Hz, 2H).

Intermediate 14

(±)-6′-Carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dioneStep A.(±)-6′-Bromo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A stirred mixture of 6-bromo-2-tetralone (17.6 g, 78.2 mmol), sodiumcyanide (9.58 g, 195 mmol), and ammonium carbonate (97.7 g, 1.02 mol) inH₂O (100 mL) and EtOH (100 mL) was heated to 70° C. for 3 h, thenallowed to cool to ambient temperature. The precipitate was collected byfiltration and washed with H₂O (5×200 mL). Drying in vacuo afforded thetitle compound as a pale solid. MS: m/z=297 (M+1).

Step B.(±)-6′-Carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

To a stirred suspension of(±)-6′-bromo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(14.9 g, 50.5 mmol) in THF (1.2 L), at −70° C., was added dropwise ethylmagnesium bromide (3.0 M in THF, 51 mL, 152 mmol). The resulting mixturewas stirred for 10 min, then tert-butyllithium (1.7 M in pentane, 180mL, 305 mmol) was added dropwise over 30 min. Stirring was continued at−70° C. for 20 min, then additional tert-butyllithium (1.7 M in pentane,60 mL, 102 mmol) was added dropwise over 10 min. After a further 30 min,CO_(2 (g)) was bubbled into the reaction mixture until LCMS analysisindicated complete reaction. The mixture was allowed to warm slowly toambient temperature and the THF was removed in vacuo. The residue wassuspended in H₂O and the solution was adjusted to pH=1-2 by the additionof conc. hydrochloric acid, to a final volume of about 500 mL. Themixture was filtered and the isolated solid was washed with H₂O (4×100mL) then dried in vacuo. Trituration of this crude solid with EtOHprovided the title compound as a pale tan solid. MS: m/z=261 (M+1).

Intermediate 15

(±)-6′-Carboxy-1-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dioneStep A.(±)-6′-Bromo-1-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A mixture of 6-bromo-2-tetralone (1.00 g, 4.44 mmol) and methylaminehydrochloride (300 mg, 4.44 mol) in H₂O (1 mL) and EtOH (1.5 mL) wasstirred at ambient temperature for 20 min. Potassium cyanide (289 mg,4.44 mmol) was added and stirring was continued for 18 h. The mixturewas added dropwise to a stirred solution of 1.0 N aqueous HCl (4.5 mL)at 0° C., then potassium cyanate (360 mg, 4.44 mmol) was addedportionwise. The stirred mixture was heated to 95° C. and conc.hydrochloric acid (0.44 mL) was added dropwise. The reaction mixture washeated at this temperature for 1 h, allowed to cool, and extracted withCH₂Cl₂ (80 mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated to dryness. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10 toprovide a crude sample of the title compound (ca. 70% pure). Triturationwith EtOH afforded the title compound as a pale solid. MS: m/z=311(M+1).

Step B.(±)-6′-Carboxy-1-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

To a stirred suspension of(±)-6′-bromo-1-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(211 mg, 0.682 mmol) in THF (30 mL), at −70° C., was added dropwiseethyl magnesium bromide (1.0 M in THF, 1.37 mL, 1.37 mmol). Theresulting mixture was stirred for 15 min, then tert-butyllithium (1.7 Min pentane, 1.61 mL, 2.73 mmol) was added dropwise. After a further 30min, CO_(2 (g)) was bubbled into the reaction mixture until LCMSanalysis indicated complete reaction. The mixture was allowed to warmslowly to ambient temperature and the THF was removed in vacuo. Theresidue was suspended in H₂O (20 mL) and the solution was adjusted topH=1-2 by the addition of 1.0 N hydrochloric acid, then it was saturatedwith NaCl_((s)). The mixture was filtered and the isolated solid waswashed with H₂O then dried in vacuo. Trituration of this crude solidwith EtOH provided the title compound as a pale tan solid. MS: m/z=275(M+1).

Intermediate 16

(±)-5′-Carboxy-spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.(±)-Spiro[imidazolidine-4,2′-indane]-2,5-dione

A stirred mixture of 2-indanone (3.0 g, 22.6 mmol), sodium cyanide (3.3g, 67.3 mmol), and ammonium carbonate (22 g, 228 mol) in H₂O (50 mL) andEtOH (50 mL) was heated to 70° C. for 3 h, then allowed to cool toambient temperature. The precipitate was collected by filtration andwashed with H₂O (5×100 mL). Drying in vacuo afforded the title compoundas a gray-brown solid. MS: m/z=202 (M+1).

Step B. (±)-5′-Bromo-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a stirred solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione(1.0 g, 4.97 mmol) in 48% HBr (30 mL) was added Br₂ (3.1 g, 19.9 mmol)and the reaction mixture was allowed to stir at ambient temperature for4 days. The reaction was poured onto ice (30 g) and H₂O (10 mL) and thesolid precipitate filtered off, washed with H₂O (4×20 mL), and dried invacuo to give the title compound as a light brown solid. MS: m/z=282(M+1).

Step C. (±)-5′-Carboxy-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a stirred suspension of(±)-5′-bromo-spiro[imidazolidine-4,2′-indane]-2,5-dione (120 mg, 0.42mmol) in THF (4 mL), at −70° C., was added dropwise ethyl magnesiumbromide (3.0 M in THF, 0.57 mL, 1.71 mmol), such that the temperaturedid not exceed −30° C. The resulting mixture was stirred for 10 min,then tert-butyllithium (1.7 M in pentane, 0.67 mL, 3.42 mmol) was addeddropwise over 5 min. Stirring was continued at −70° C. for 20 min, thenCO_(2 (g)) was bubbled into the reaction mixture until LCMS analysisindicated complete reaction. The mixture was allowed to warm slowly toambient temperature and the THF was removed in vacuo. The residue wassuspended in 5 mL 0.5 M HCl and the solution was adjusted to pH=1-2 bythe addition of conc. hydrochloric acid, to a final volume of about 10mL. The precipitate was filtered and the isolated solid was washed withH₂O (4×10 mL) then dried in vacuo to provide the title compound as abrown solid. MS: m/z=247 (M+1).

Intermediate 17

(±)-6′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A stirred mixture of(±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(1.50 g, 5.76 mmol), and sodium azide (749 mg, 11.53 mmol) in conc.H₂SO₄ (30 mL) was heated to 50° C. for 2 h, then allowed to cool toambient temperature. The mixture was adjusted to pH 8 by addition of 6 Naqueous NaOH and concentrated in vacuo to precipitate a solid. Theprecipitate was collected by filtration and washed extensively with H₂O.Drying in vacuo afforded the title compound as a light brown solid. MS:m/z=232 (M+1).

Intermediate 18

(±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.(±)-5′-Nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

A solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.0 g,14.8 mmol) in conc. nitric acid (33 mL) was stirred at ambienttemperature for 1 h. The reaction was then poured onto crushed ice andthe resultant solid was isolated by filtration. The crude material wasrecrystallized from ethanol to give the title compound as a yellowsolid. MS: m/z=248 (M+1).

Step B. (±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a suspension of(±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16mmol) in EtOAc (100 μL) and MeOH (100 mL) was added 10% Pd/C (400 mg)and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1h, the catalyst was filtered off and the filtrate was concentrated toyield 1.50 g (97%) of the title compound as a pale brown solid. MS:m/z=218 (M+1).

Example 1

N-[(4R)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide

(4R)-Amino-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine is preparedaccording methods described in R. Freidinger et al, EP 0523 846A2(1993). Triethylamine (2 eq) is added to a solution of(4R)-amino-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine (1 eq) and4-nitrophenyl chloroformate (1 eq) in tetrahydrofuran is added at 0° C.After 30 min,2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumdichloride (1.5 eq), triethylamine (3 eq) and dichloromethane are addedand the mixture allowed to warm to ambient temperature. After 18 h, thereaction is concentrated. Purification is by reverse phase HPLC (C-18,90% water/acetonitrile 100% acetonitrile with 0.1% trifluoroaceticacid).

Example 2

N-[(4R)-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide

The title compound is prepared from(4R)-amino-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepineaccording to the reference and procedure of Example 1, using methodscommonly known to those in the art.

Example 3

N-[(4R)-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide

The title compound is prepared fromN-[(4R)-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(M. G. Bock et al, J. Med. Chem. 1988, 31(1), 176-181)) and2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumdichloride according to the procedure of Example 1.

Example 4

N-[(4R)-2-methyl-6-phenyl-2,4-dihydro-1H-imidazo[1,2-a][1,4]-benzodiazepin-4-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide

The title compound is prepared fromN-[(4R)-2-methyl-6-phenyl-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepine(M. G. Bock et al, Bioorg. Med. Chem. Lett., 1994, 2(9), 987-998) and2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumdichloride according to the procedure of Example 1.

Example 5

4-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-N-[(4R)-6-phenyl-4H-tetrazolo[1,5-a][1,4]benzodiazepin-4-yl]piperidine-1-carboxamide

The title compound is prepared fromN-[(4R)-6-phenyl-4H-tetrazolo[1,5-a][1,4]benzodiazepine (R. Freidingeret al, EP 0523846A2 (1993)) and2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumdichloride according to the procedure of Example 1.

Example 6

4-(2,4-Dioxoimidazolidin-1-yl)-N-[(4R)-1-methyl-6-phenyl-4H-imidazo[1,2-a]benzodiazepine-4-yl]piperidine-1-carboxamide

The title compound is prepared from(4R)-amino-1-methyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine and1-piperidin-4-ylimidazolidine-2,4-dione according to the proceduredescribed in Example 1.

Examples 7-21

Following procedures described above, and using methods known to thosein the art, the examples in Table 1 can be prepared using the notedintermediates.

TABLE 1

Inter- Example R mediate 7

3 8

4 9

5 10

6 11

7 12

8 13

10 14

11 15

12 16

13 17

14 18

15 19

16 20

17 21

18

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of the Formula I:

wherein: Z is selected from:

D is independently selected from N and C(R¹); R¹ is independentlyselected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆cycloalkyl, and heterocycle, unsubstituted or substituted with one ormore substituents each independently selected from: a) C₁₋₆ alkyl, b)C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5substituents each independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1-5 substituents each independentlyselected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5substituents each independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹,p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u)N(R¹⁰)(CO)NR⁴R¹¹, and, v) O(CO)R⁴; 2) aryl or heteroaryl, unsubstitutedor substituted with one or more substituents each independently selectedfrom: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,d) heteroaryl, unsubstituted or substituted with 1-5 substituents eachindependently selected from R⁴, e) heterocycle, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k)(CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o)N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN,t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹, and v) O(CO)R⁴; where any twoindependent R¹ and the atom or atoms to which they are attachedoptionally join to form a ring selected from C₃₋₆ cycloalkyl, aryl,heterocycle, and heteroaryl; R² is independently selected from H and: 1)C₁₋₆ alkyl, 2) C₃₋₆ cycloalkyl, 3) aryl, unsubstituted or substitutedwith 1-5 substituents where the substituents are independently selectedfrom R⁴, 4) heteroaryl, unsubstituted or substituted with 1-5substituents where the substituents are independently selected from R⁴,5) heterocycle, unsubstituted or substituted with 1-5 substituents wherethe substituents are independently selected from R⁴, 6) (F)_(p)C₁₋₃alkyl, 7) halogen, 8) OR⁴, 9) O(CH₂)_(s)OR⁴, 10) CO₂R⁴, 11) (CO)NR¹⁰R¹¹,12) O(CO)NR¹⁰R¹¹, 13) N(R⁴)(CO)NR¹⁰R¹¹, 14) N(R¹⁰)(CO)R¹¹, 15)N(R¹⁰)(CO)OR¹¹, 16) SO₂NR¹⁰R¹¹, 17) N(R¹⁰) SO₂R¹¹, 18) S(O)_(m)R¹⁰, 19)CN, 20) NR¹⁰R¹¹, 21) N(R¹⁰)(CO)NR⁴R¹¹, and 22) O(CO)R⁴; where any twoindependent R² on the same or adjacent atoms optionally join to form aring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl,cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl andpiperazinyl; R⁷ is selected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted orsubstituted with one or more substituents independently selected from:a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substitutedwith 1-5 substituents where the substituents are independently selectedfrom R⁴, d) heteroaryl, unsubstituted or substituted with 1-5substituents where the substituents are independently selected from R⁴,e) heterocycle, unsubstituted or substituted with 1-5 substituents wherethe substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹,l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o)N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN,t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹, v) O(CO)R⁴; and 2) aryl or heteroaryl,unsubstituted or substituted with one or more substituents independentlyselected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstitutedor substituted with 1-5 substituents where the substituents areindependently selected from R⁴, d) heteroaryl, unsubstituted orsubstituted with 1-5 substituents where the substituents areindependently selected from R⁴, e) heterocycle, unsubstituted orsubstituted with 1-5 substituents where the substituents areindependently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h)OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m)N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q)N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹,and v) O(CO)R⁴; R⁴ is independently selected from: H, C₁₋₆ alkyl,(F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy; M is—NH— or is a bond; K is —CH₂— or is a bond; W is O, NR⁴ or C(R⁴)₂; X isC or S; Y is O, (R⁴)₂, NCN, NSO₂CH₃ or NCONH₂, or Y is O₂ when X is S;R⁶ is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from R⁴, d)heteroaryl, unsubstituted or substituted with 1-5 substituents eachindependently selected from R⁴, e) heterocycle, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k)(CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o)N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN,t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹, and v) O(CO)R⁴; J is a bond, C(R⁶)₂, Oor NR⁶; V is selected from a bond, C(R⁶)₂, O, S(O)_(m), NR⁶,C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), C(R⁶)₂—N(R⁶), C(R⁶)═N,N(R⁶)—C(R⁶)₂, N═C(R⁶),and N(R⁶)—N(R⁶); G-L is selected from: N, N—C(R⁶)₂, C═C(R⁶), C═N, C(R⁶),C(R⁶)—C(R⁶)₂, C(R⁶)—C(R⁶)₂—C(R⁶)₂, C═C(R⁶)—C(R⁶)₂, C(R⁶)—C(R⁶)═C(R⁶),C(R⁶)—C(R⁶)₂—N(R⁶), C═C(R⁶)—N(R⁶), C(R⁶)—C(R⁶)═N, C(R⁶)—N(R⁶)—C(R⁶)₂,C═N—C(R⁶)₂, C(R⁶)—N═C(R⁶), C(R⁶)—N(R⁶)—N(R⁶), C═N—N(R⁶),N—C(R⁶)₂—C(R⁶)₂, N—C(R⁶)═C(R⁶), N—C(R⁶)₂—N(R⁶), N—C(R⁶)═N,N—N(R⁶)—C(R⁶)₂ and N—N═C(R⁶); Q is independently selected from: (1)═C(R^(7a))—, (2) —C(R^(7a))₂—, (3) —C(═O)—, (4) —S(O)_(m)—, (5) ═N—, (6)—N(R^(7a))—, and, (7) a bond; T is independently selected from: (1)═C(R^(7b))—, (2) —C(R^(7b))₂—, (3) —C(═O)—, (4) —S(O)_(m)—, (5) ═N—, (6)—N(R^(7b))—, and (7) a bond; R³ is independently selected from H,substituted or unsubstituted C₁-C₃ alkyl, F, CN and CO₂R⁴; R^(7a) andR^(7b) are each independently selected from R², where R^(7a) and R^(7b)and the atom or atoms to which they are attached optionally join to forma ring selected from C₃₋₆ cycloalkyl, aryl, heterocycle, and heteroaryl,which ring is unsubstituted or substituted with 1-10 substituents eachindependently selected from R⁶; R¹⁰ and R¹¹ are independently selectedfrom: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heteroaryl, and benzyl, unsubstituted or substituted with halogen,hydroxy or C₁-C₆ alkoxy, where R¹⁰ and R¹¹ optionally join to form aring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,or morpholinyl, which is ring is unsubstituted or substituted with 1-5substituents each independently selected from R⁴; p is 0 to 2q+1, for asubstituent with q carbons; m is 0, 1 or 2; s is 1, 2 or 3; the dashedline indicates the optional presence of a double bond; andpharmaceutically acceptable salts and individual diastereomers thereof.2. A compound of the Formula Ib:

wherein: D is independently selected from N and C(R¹); R¹ isindependently selected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃₋₆ cycloalkyl, and heterocycle, unsubstituted or substitutedwith one or more substituents each independently selected from: a) C₁₋₆alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with1-5 substituents each independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1-5 substituents each independentlyselected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5substituents each independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹,p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u)N(R¹⁰)(CO)NR⁴R¹¹, and, v) O(CO)R⁴; 2) aryl or heteroaryl, unsubstitutedor substituted with one or more substituents each independently selectedfrom: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,d) heteroaryl, unsubstituted or substituted with 1-5 substituents eachindependently selected from R⁴, e) heterocycle, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k)(CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o)N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN,t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹, and v) O(CO)R⁴; where any twoindependent R¹ and the atom or atoms to which they are attachedoptionally join to form a ring selected from C₃₋₆ cycloalkyl, aryl,heterocycle, and heteroaryl; R² is independently selected from H and: 1)C₁₋₆ alkyl, 2) C₃₋₆ cycloalkyl, 3) aryl, unsubstituted or substitutedwith 1-5 substituents where the substituents are independently selectedfrom R⁴, 4) heteroaryl, unsubstituted or substituted with 1-5substituents where the substituents are independently selected from R⁴,5) heterocycle, unsubstituted or substituted with 1-5 substituents wherethe substituents are independently selected from R⁴, 6) (F)_(p)C₁₋₃alkyl, 7) halogen, 8) OR⁴, 9) O(CH₂)_(s)OR⁴, 10) CO₂R⁴, 11) (CO)NR¹⁰R¹¹,12) O(CO)NR¹⁰R¹¹, 13) N(R⁴)(CO)NR¹⁰R¹¹, 14) N(R¹⁰)(CO)R¹¹, 15)N(R¹⁰)(CO)OR¹¹, 16) SO₂NR¹⁰R¹¹, 17) N(R¹⁰) SO₂R¹¹, 18) S(O)_(m)R¹⁰, 19)CN, 20) NR¹⁰R¹¹, 21) N(R¹⁰)(CO)NR⁴R¹¹, and 22) O(CO)R⁴; where any twoindependent R² on the same or adjacent atoms optionally join to form aring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl,cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl andpiperazinyl; R⁷ is selected from: 1) aryl unsubstituted or substitutedwith one or more substituents independently selected from: a) C₁₋₆alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with1-5 substituents where the substituents are independently selected fromR⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from R⁴, e)heterocycle, unsubstituted or substituted with 1-5 substituents wherethe substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹,l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o)N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN,t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹, and v) O(CO)R⁴; R⁴ is independentlyselected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heteroaryl and benzyl, unsubstituted or substituted with halogen,hydroxy or C₁-C₆ alkoxy; Q is independently selected from: (1)═C(R^(7a))—, (2) —C(R^(7a))₂—, (3) —C(═O)—, (4) —S(O)_(m)—, (5) ═N—, and(6) —N(R^(7a))—; T is independently selected from: (1) ═C(R^(7b))—, (2)—C(R^(7b))₂—, (3) —C(═O)—, (4) —S(O)_(m)—, (5) ═N—, and (6) —N(R^(7b))—;R³ is independently selected from H, substituted or unsubstituted C₁-C₃alkyl, F, CN and CO₂R⁴; R^(7a) and R^(7b) are each independentlyselected from R², where R^(7a) and R^(7b) and the atom or atoms to whichthey are attached optionally join to form a ring selected from C₃₋₆cycloalkyl, aryl, heterocycle, and heteroaryl, which ring isunsubstituted or substituted with 1-10 substituents each independentlyselected from R⁶; R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl,unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy,where R¹⁰ and R¹¹ optionally join to form a ring selected from:azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,which is ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from R⁴; p is 0 to 2q+1, for a substituent with qcarbons; m is 0, 1 or 2; s is 1, 2 or 3; and pharmaceutically acceptablesalts and individual diastereomers thereof.
 3. A compound of the FormulaIc:

wherein: D is independently selected from N and C(R¹); R¹ isindependently selected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃₋₆ cycloalkyl, and heterocycle, unsubstituted or substitutedwith one or more substituents each independently selected from: a) C₁₋₆alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with1-5 substituents each independently selected from R⁴, d) heteroaryl,unsubstituted or substituted with 1-5 substituents each independentlyselected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5substituents each independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl,g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l)O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹,p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u)N(R¹⁰)(CO)NR⁴R¹¹, and, v) O(CO)R⁴; 2) aryl or heteroaryl, unsubstitutedor substituted with one or more substituents each independently selectedfrom: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,d) heteroaryl, unsubstituted or substituted with 1-5 substituents eachindependently selected from R⁴, e) heterocycle, unsubstituted orsubstituted with 1-5 substituents each independently selected from R⁴,f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k)(CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o)N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰) SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN,t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹, and v) O(CO)R⁴; where any twoindependent R¹ and the atom or atoms to which they are attachedoptionally join to form a ring selected from C₃₋₆ cycloalkyl, aryl,heterocycle, and heteroaryl; R⁴ is independently selected from: H, C₁₋₆alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy; Q isindependently selected from: (1) ═C(R^(7a))—, (2) —C(R^(7a))₂—, (3)—C(═O)—, (4) —S(O)_(m)—, (5) ═N—, and (6) —N(R^(7a))—; T isindependently selected from: (1) ═C(R^(7b))—, (2) —C(R^(7b))₂—, (3)—C(═O)—, (4) —S(O)_(m)—, (5) ═N—, and (6) —N(R^(7b))—; R^(7a) and R^(7a)are each independently selected from R², where R^(7a) and R^(7a) and theatom or atoms to which they are attached optionally join to form a ringselected from C₃₋₆ cycloalkyl, aryl, heterocycle, and heteroaryl, whichring is unsubstituted or substituted with 1-10 substituents eachindependently selected from R⁶; R¹⁰ and R¹¹ are independently selectedfrom: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,heteroaryl, and benzyl, unsubstituted or substituted with halogen,hydroxy or C₁-C₆ alkoxy, where R¹⁰ and R¹¹ optionally join to form aring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,or morpholinyl, which is ring is unsubstituted or substituted with 1-5substituents each independently selected from R⁴; p is 0 to 2q+1, for asubstituent with q carbons; m is 0, 1 or 2; s is 1, 2 or 3; andpharmaceutically acceptable salts and individual diastereomers thereof.4. The compound of claim 1, wherein J is a bond, V is a bond and Z isZ1.
 5. The compound of claim 1, wherein J is a bond, V is a bond, Z isZ1 and T is —C(═O)—.
 6. The compound of claim 1, wherein G-L is N, and Zis Z2.
 7. The compound of claim 1, wherein G-L is N—C(R⁶)₂, and Z is Z2.8. The compound of claim 1, wherein G-L is C═C(R⁶), and Z is Z2.
 9. Thecompound of claim 1, wherein G-L is C═N, and Z is Z2.
 10. The compoundof claim 1, wherein G-L is N—C(R⁶)₂—C(R⁶)₂ and Z is Z2.
 11. The compoundof claim 1, wherein J is a bond, V is a bond, Z is Z1, Q is —N(R^(7a))—,and T is —C(═O)—.
 12. The compound of claim 1, wherein J is a bond, V isa bond, Z is Z1, Q is —C(R^(7a))₂—, and T is —C(═O)—.
 13. The compoundof claim 1, wherein J is a bond, Visa bond, Z is Z1, Q is —N═, and T is═C(R^(7a))—.
 14. The compound of claim 1, wherein J is a bond, V is abond, Z is Z1, Q is —C(R^(7a))₂—, and T is —C(R^(7b))₂—.
 15. Thecompound of claim 1, wherein J is a bond, Visa bond, Z is Z1, Q is—C(R^(7a))═, T is ═C(R^(7b))—, and the atoms to which R^(7a) and R^(7b)are attached are joined together to form a benzene, pyridine, or diazinering.
 16. The compound of claim 1, wherein J is a bond, V is C(R⁶)₂, Zis Z1, Q is —C(R^(7a))═, T is ═C(R^(7b))—, and the atoms to which R^(7a)and R^(7b) are attached are joined together to form a benzene orpyridine ring.
 17. A compound of claim 1 which is selected from:

and pharmaceutically acceptable salts and individual stereoisomersthereof.
 18. A pharmaceutical composition which comprises an inertcarrier and the compound of claim 1.